Patients are often required to take multiple medications for the prophylaxis or treatment of diseases. Often patients are required to take different medications at different specified times. This results in patient inconvenience and consequently patient non-compliance to the prescribed dosage regimen.
A combination of two different medications could be taken at specified different times to obtain the desired control on the symptoms of the disease or a measurable indicator of the disease condition. For example, a specific antidiabetic agent may be orally administered at a specific time period prior to food intake to control post-prandial glucose and a second antidiabetic agent may be more useful in controlling glucose levels when given with food. However, there are no prior art spaced drug delivery systems that enable one to administer medications in a convenient manner. Thus, there is a need for a method of administration of two or more therapeutically active agents comprising orally administering to a patient a spaced drug delivery system, wherein at least one first therapeutically active agent is released immediately upon oral administration of the spaced drug delivery system and at least one second therapeutically active agent is released as a pulse at a predetermined time after oral administration, wherein the two or more therapeutic agents act on the disease condition by similar or dissimilar, but complementary mechanisms, to control the symptoms of the disease, or a measurable indicator of the disease condition, and further wherein the time of release of the two or more therapeutically active agents is designed to provide desired control on the disease condition.
A combination of two different medications could also be taken at specified different times when one medication is required to be given on an empty stomach and the other with meals. Reasons for giving certain medications on an empty stomach or with meals are well known to those skilled in the art and include for example, different rate or extent of absorption of the drug on an empty stomach versus in presence of food, difference in extent of degradation of the drug in gastric fluids when given with food versus without food, gastric irritation due to the drug and thus, there is a need for a method of administration of two or more therapeutically active agents comprising orally administering to a patient a spaced drug delivery system at a specified time prior to food intake by the patient, wherein at least one therapeutically active agent is released immediately upon oral administration of the spaced drug delivery system and at least one therapeutically active agent is released as a pulse after a delay at about the time when food is taken i.e. either immediately prior to meals, or at the time of meals, or after meals.
Maximum reduction in post-prandial blood-glucose can be obtained by administering antidiabetic agents such as glipizide about 30 minutes before meals, and hence, an immediate release of such antidiabetic agents is essential. On the other hand, an antidiabetic agent such as metformin is given with food. A spaced drug delivery system that immediately releases an antidiabetic agent, such as glipizide, after oral administration of the system prior to meals, and releases as a pulse, after a delay, antidiabetic agents such as metformin, at the time the meal is taken, would provide improved patient compliance to the dosage regimen and optimum clinical benefits.
Non-insulin dependent diabetes mellitus (NIDDM), also known as maturity-onset diabetes or diabetes mellitus type 2, is a frequent metabolic disease and the main cause of hyperglycemia. It is a heterogeneous disease with complex, unclarified metabolic aspects. Insulin secretion may appear normal or even excessive, but it is insufficient to compensate for insulin resistance. The disease is characterized by three main abnormalities of metabolism contributing to hyperglycemia. These include the partial or complete decrease in insulin secretion, resistance of the peripheral tissues to insulin and increased hepatic production of glucose in fasting conditions. Insulin resistance may also be responsible for the obesity associated with NIDDM, although obesity itself has a reciprocal effect on insulin resistance; excess weight worsens insulin resistance, while weight loss lowers blood glucose levels. Diet and physical exercise cause a reduction in insulin-resistance and lead to an improvement in the pancreas deficit over a period of time.
The treatment goal of NIDDM is to normalize blood-glucose level in an attempt to prevent or reduce complications that may arise due to chronic hyperglycemia. The effect of regular exercise supplementing diet in patients with NIDDM causes a reduction in insulin-resistance and leads to an improvement in the pancreas deficit over a period of time. When these provisions are not sufficient, a pharmacological agent needs to be taken for control of hyperglycemia. Oral medications work either to reduce the body's resistance to its own insulin, or work to increase insulin secretion to meet the demand. Sulfonylureas and biguanides have been used in oral antidiabetic therapy. Other classes of oral antidiabetic agents include the alpha-glucosidase inhibitors, aldose reductase inhibitors, thiazolidinediones, insulin secretagogues and others. The use of these classes of compounds in monotherapy has been effective in obtaining a glycometabolic control in diabetic patients.
Biguanide derivatives like metformin, phenformin and buformin, generally in the form of their hydrochloride salt, have been used as anti-hyperglycemic agents in the treatment of non-insulin dependent diabetes mellitus. The mechanism of action of the drugs belonging to this class includes reduction in hepatic glucose production, decrease in intestinal absorption of glucose, and increase in glucose uptake and utilization. Biguanides improve glucose tolerance in patients with diabetes mellitus type 2, lowering both basal and post-prandial plasma glucose. With biguanide therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Although phenformin is still used widely as an anti-hyperglycemic agent, metformin is the preferred biguanide, as it exerts a better normoglycemic action with a lower risk of lactic acidosis—a common side-effect with phenformin therapy. Metformin is also known to lower blood triglyceride levels and assist in weight reduction.
The sulfonyl ureas used in the treatment of diabetes mellitus type 2 include acetohexamide, carbutamide, chlorpropamide, glipizide, glyburide (glibenclamide), glimepiride, gliclazide, glibomuride, gliquidone, glisoxepid, glyhexamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, etc. These sulfonyl ureas are used as their bases and not as salts. The mechanism of action of these drugs involves lowering of blood glucose concentration mainly by stimulating release of endogenous insulin from beta cells of the pancreas, and thus they act as hypoglycemic agents. The sulfonyl ureas are used as an adjunct to diet for the management of non-insulin dependent diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet alone. To achieve maximum reduction in post-prandial blood-glucose concentration, the sulfonyl urea is administered 30 minutes prior to each meal.
The 55th edition of the Physicians' Desk Reference, copyright 2001, suggests that the monotherapy with metformin hydrochloride, commercially available under the trade name Glucophage® from Bristol-Myers Squibb Co., may be effective in patients who have not responded to sulfonyl ureas or who have only a partial response to sulfonyl ureas or who have ceased to respond to sulfonyl ureas. In such patients, if adequate glycemic control is not attained with Glucophage® monotherapy, the combination of Glucophage® and a sulfonyl urea may have a synergistic effect. Also, monotherapy with the sulfonyl ureas has been found to give a positive response, which lasts for 4-5 years, but it becomes ineffective in a large number of patients over a period of time. This is referred to as the “secondary failure” associated with the oral therapy with hypoglycemic agents. In both these cases, a combination of biguanides and sulfonyl ureas is used. The biguanides are able to act on insulin resistance but cannot stimulate insulin secretion, while the sulfonyl ureas can stimulate insulin release but are unable to act on insulin resistance. A combination therapy of a biguanide and a sulfonyl urea has a synergistic effect on glucose control, since both agents act by different but complementary mechanisms.
Diabetes mellitus is a chronic disease with diverse pathologic manifestations and is accompanied by lipid metabolism disorders and circulatory disorders, as well as glycometabolism disorders. As a result, the disease tends to progress entailing complications in many cases. Therefore, it is necessary to select the drug of choice for the prevailing disease state in each individual case. However, this selection is often difficult in clinical settings because single use of each individual drug cannot bring sufficient effects in some disease states and there are various problems such as side effects caused by an increased dose or long-term administration of a single drug or agent. Hence, there is a need to include combination therapy in NIDDM.
Alpha glucosidases are essential for the breakdown of starches, dextrins, maltose and sucrose. Alpha glucosidase inhibitors act by delaying glucose absorption from a carbohydrate load by inhibiting the glucosidases. The compounds of this class have the ability to prevent or attenuate diabetic nephropathic lesions. The common drugs of this class include acarbose, miglitol, emiglitate and voglibose. Inhibition of alpha glucosidase causes a delay in the digestion of sucrose and other polysaccharides, thus retarding the rate of absorption of glucose and fructose. Acarbose is a complex oligosaccharide, which competitively inhibits intestinal brush border alpha glucosidases including glucoamylase, sucrase, maltase and isomaltase. It is the preferred alpha glucosidase inhibitor for use as an antihyperglycemic because it does not cause hypoglycemia. The drug also has weight lowering action. The alpha glucosidase inhibitors may be administered along with other oral antidiabetic drugs for a better control on the blood-glucose levels. The 55th edition of the Physicians' Desk Reference, copyright 2001, states that acarbose diminishes the insulinotropic and weight increasing effects of sulfonyl ureas, when administered together.
The thiazolidinediones is another class of antidiabetic agents which are thought to act by enhancing insulin action, thus promoting glucose utilization in the peripheral tissues, possibly by stimulating non-oxidative glucose metabolism in muscle, and suppressing gluconeogenesis in the liver. The drugs belonging to this class stimulate adipogenesis and reduce plasma triglyceride and free fatty acid concentrations. The examples of thiazolidinediones commonly used in diabetes mellitus include troglitazone, pioglitazone, rosiglitazone, ciglitazone, darglitazone and englitazone. Although thiazolidinediones enhance insulin action at the cellular level, they do not stimulate insulin release nor do they mimic its action. The therapeutic benefits of thiazolidinedione treatment depend on the availability of adequate amounts of insulin. The addition of a thiazolidinedione antidiabetic agent to concurrent sulfonyl urea treatment provides a balance of stimulated release of insulin while ameliorating insulin resistance.
A new class of insulinotropic agents (secretagogues) called metglitinide analogs or prandial glucose regulators, is now being used in the management of NIDDM. The compounds of this class are fast acting, short acting, non-sulfonyl urea, oral hypoglycemic agents that act by regulating prandial glucose. The prandial glucose regulation is aimed at restoring the first-phase insulin response that follows consumption of a meal, which is missing in NIDDM patients. Repaglinide, the most commonly used agent of this class, provides a tighter glycemic control, while reducing the risk of hypoglycemic events. The drug lowers blood-glucose levels by stimulating the secretion of insulin from the pancreas. This action is dependent on the functioning β-cells in the pancreatic islets. Repaglinide closes ATP-dependent potassium channels in the β-cell membrane by binding at characterisable sites. This potassium channel blockade depolarizes the β-cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion-channel mechanism is highly tissue selective, with low affinity for heart and skeletal muscle. Repaglinide is rapidly absorbed and rapidly eliminated, ensuring quick return of post-prandial insulin levels to preprandial levels. Insulin release is glucose dependent and diminishes at low glucose concentrations. Repaglinide also offers increased mealtime flexibility and safety. As a result of the short plasma half-life and lack of accumulation of repaglinide with repeated dosing, the risk of between-meal and nocturnal hypoglycemia is substantially reduced. The drug acts synergistically with biguanides and thiazolidinediones, especially metformin and troglitazone. The dose of repaglinide ranges from 0.5 to 4 mg, administered before each meal.
The prior art includes a number of systems that use a combination of antidiabetic agents for the treatment of non-insulin dependent diabetes mellitus. U.S. Pat. No. RE 37330 (a reissue of U.S. Pat. No. 5,922,769) claims a method of treating non-insulin dependent diabetes mellitus in cases of secondary failure to a treatment utilizing a combination of glibenclamide-metformin hydrochloride, in a weight ratio higher than 1:100, comprising administering to a subject in need of same a combination of glibenclamide and metformin, expressed as the hydrochloride, in a weight ratio of 1:100. The patent also discloses the results of a clinical study, which indicates that the maximum dose of glibenclamide, which does not cause any side-effects, is 15 mg/day, while that for metformin is 1500 mg/day, and that the use of such a combination in a ratio lower than that claimed would result in formulations that do not attain the optimum therapeutic effect. The patent claims the combination of glibenclamide and metformin in a tablet form. The patent does not disclose a formulation wherein the sulfonyl urea is released immediately and the biguanide is released after a delay period, particularly after a predetermined delay period.
U.S. Pat. No. 6,031,004 ('004) discloses the use of a combination of novel salts of metformin and glyburide, in the treatment of diabetes mellitus type 2. In this invention, both metformin salt and glyburide are released immediately. The patent does not disclose a composition wherein the sulfonyl urea is released immediately and the biguanide is released after a delay period, particularly after a predetermined delay period.
U.S. Pat. No. 6,099,862 ('862) claims a controlled release pharmaceutical tablet which consists essentially of (a) a core consisting essentially of: (i) metformin or a pharmaceutically acceptable salt thereof, (ii) glipizide, (iii) polyvinylpyrrolidone, and (iv) sodium lauryl sulfate, (b) optionally a seal coat around the core, (c) a semipermeable membrane coating covering said core comprising—(i) cellulose acetate, (ii) polyethylene glycol with an average molecular weight between 380 and 420, and (iii) a plasticiser, and (d) at least one passageway in the semipermeable membrane to allow the release of the metformin and glipizide from the core to the environment of use to provide therapeutic levels of metformin and glipizide from twelve to twenty-four hour periods. In this invention, both metformin salt and glipizide are released slowly upon oral administration. The patent does not disclose a composition wherein the sulfonyl urea is released immediately and the biguanide is released after a delay period, particularly after a predetermined delay period.
PCT applications WO 98/57649 and WO 99/03476 both claim a combination of an insulin sensitiser such as a thiazolidinedione and an insulin secretagogue such as a sulfonyl urea. The system of the PCT application WO 99/03477 claims a method for the treatment of diabetes mellitus and conditions associated with it, using a combination of an insulin sensitiser, an insulin secretagogue and a biguanide antihyperglycemic agent. The insulin sensitiser used in this combination is a thiazolidinedione like troglitazone, ciglitazone, rosiglitazone, pioglitazone or englitazone, and the insulin secretagogue is a sulfonyl urea or repaglinide. The application thus claims the combination of a thiazolidinedione, a sulfonyl urea or repaglinide, and a biguanide. The application discloses that the claimed combinations exhibit synergism when given as a unit dosage form, and therefore the amount of each agent required is reduced. However, all the agents are released in a conventional manner, thereby reducing the flexibility of administration.
PCT application WO 99/03478 claims a method for the treatment of diabetes mellitus and conditions associated with it, using a combination of an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor. The insulin sensitiser used is a thiazolidinedione, the insulin secretagogue is a sulfonyl urea or repaglinide, while the alpha glucosidase inhibitor is selected from acarbose, emiglitate and miglitol. The application discloses that such a combination has a beneficial effect on the glycemic control as a result of a synergistic effect, and also has minimum side effects. The invention, however, does not provide spaced drug delivery of a combination of two or more antidiabetic agents, wherein one antidiabetic agent is released immediately and the other antidiabetic agent(s) is/are released at a predetermined time interval.
The system of the U.S. Pat. No. 6,011,049 claims a composition comprising a combination of synergistic amounts of a sulfonyl urea, a thiazolidinedione (glitazone) antidiabetic agent and a biguanide. The patent teaches that since the unstimulated insulin secretory capacity of the β-cells is very low in NIDDM, reversing insulin resistance alone would be of partial benefit. Therefore, the system maintains a level of stimulated insulin secretion with a sulfonyl urea while adding glitazone to improve insulin sensitivity, thereby providing a level of glycemic control unattainable by either medication alone. However, the invention does not provide a spaced drug delivery system of a combination of the two or more antidiabetic agents.
The system claimed in the PCT application WO 98/56378 uses a short-acting hypoglycemic agent capable of stimulating insulin secretion from β-cells, for the manufacture of a medicament adapted to stimulate meal-related insulin secretion, for the treatment of post-prandial hyperglycemia in NIDDM patients. The system uses repaglinide or a combination of repaglinide with long-acting hypoglycemic agents like metformin, a sulfonyl urea or troglitazone. The application teaches that repaglinide stimulates endogenous secretion of insulin in connection with meals, while metformin enhances tissue sensitivity towards insulin, the combination providing a significant improvement in glycemic control. The combination is administered prandially. The invention, however, does not provide spaced drug delivery of a combination of two or more antidiabetic agents, wherein one antidiabetic agent is released immediately and the other antidiabetic agent(s) is/are released at a predetermined time interval.
U.S. Pat. No. 6,166,043 ('043) claims a method for reducing the amounts of active components administered to a diabetic patient, which comprises administering a therapeutically effective amount of an insulin sensitivity enhancer in combination with a biguanide. The insulin sensitivity enhancer claimed in the system is a thiazolidinedione selected from pioglitazone and troglitazone, while the biguanide is selected from metformin, phenformin and buformin. The combination is administered as an admixture or the agents are administered independently, wherein both the agents are released immediately.
U.S. Pat. No. 6,172,090 ('090) claims a method for reducing side effects of active components administered to a diabetic patient, which comprises administering to the said patient a therapeutically effective amount of an insulin sensitivity enhancer in combination with a biguanide. Similar to the '043 system, the patent claims a combination of a thiazolidinedione like pioglitazone or troglitazone, and a biguanide like metformin, phenformin or buformin, which is administered independently or as an admixture. In this invention, the thiazolidinedione and the biguanide are available immediately after oral administration of the dosage form as a conventional release.
U.S. Pat. No. 6,153,632 ('632) claims a composition for the treatment of diabetes mellitus comprising a therapeutic amount of an insulin sensitiser and a therapeutic amount of an antidiabetic agent, the latter being selected from the group consisting of orally ingestible insulin, injectable insulin, a sulfonyl urea, a biguanide and an alpha glucosidase inhibitor. The insulin sensitiser used in the invention is a thiazolidinedione. Both the antidiabetic agents are released immediately after oral administration of the composition in a conventional manner.
PCT application WO 98/57634 ('634) claims a method for treating diabetes mellitus and conditions associated with it comprising administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser and a biguanide antihyperglycemic agent. The insulin sensitiser used in the invention is a thiazolidinedione. In this invention both the antidiabetic agents are released immediately.
PCT application WO 00/28989 claims a pharmaceutical composition comprising an insulin sensitiser and another antidiabetic agent, and a pharmaceutically acceptable carrier therefore, wherein the composition is arranged to provide a modified release of at least one of the insulin sensitiser and the other antidiabetic agent. The modified release claimed may be a delayed release using gastric resistant formulation, or a sustained release using disintegrating, non-disintegrating or eroding matrices, or a controlled release formulation. The insulin sensitiser used in the invention is a thiazolidinedione, while the other antidiabetic agent is selected from an alpha glucosidase inhibitor, biguanide and an insulin secretagogue, the insulin secretagogue being a sulfonyl urea, repaglinide or nateglinide. The application teaches that the combination provides an advantageous delivery of the antidiabetic agents, maintaining effective glycemic control and has no observed adverse effects. The invention, however, does not provide spaced drug delivery of a combination of two or more antidiabetic agents, wherein one antidiabetic agent is released immediately and the other antidiabetic agent(s) is/are released at a predetermined time interval.
A plethora of prior arts relate to pharmaceutical compositions that release a drug after a delay. Some prior arts that relate to release of drug after a predetermined time include U.S. Pat. No. 3,247,066; Irish patent application no IE 902533; U.S. Pat. Nos. 4,871,549; 5,229,131; PCT Publication no WO 99/18938 and PCT Publication no WO 00/74655. All of these relate to systems comprising a core that swells upon imbibing fluid from the surrounding and a coat that ruptures due to the pressure exerted upon it by the swelling core. However, none of these prior arts disclose a spaced drug delivery system designed to provide desired control on the disease condition, comprising                a. a first composition comprising one or more first therapeutically active agents, and        b. a second composition comprising one or more second therapeutically active agents,wherein at least one first therapeutically active agent is released immediately upon oral administration of the spaced drug delivery system, and at least one second therapeutically active agent is released as a pulse at a predetermined time after oral administration, wherein the two or more therapeutic agents act on the disease condition by similar or dissimilar, but complementary mechanisms, to control the symptoms of the disease, or a measurable indicator of the disease condition, and further wherein the time of release of the two or more therapeutically active agents is designed to provide desired control on the disease condition. More specifically and particularly, none of the prior arts suggest that it would benefit the treatment of diabetes mellitus by oral administration of a spaced drug delivery system comprising one or more therapeutically active antidiabetic agents wherein at least one first therapeutically active antidiabetic agent is released immediately upon oral administration of the spaced drug delivery system, and at least one second therapeutically active antidiabetic agent is released as a pulse at a predetermined time after oral administration. Further, they do not disclose a spaced drug delivery system that immediately releases at least one first therapeutically active agent after oral administration of the spaced drug delivery system at a specified time prior to meals and releases at least one second therapeutically active antidiabetic agent at about the time the meal is taken. Prior arts such as U.S. Pat. No. 3,247,066, European Patent Application 1123700, U.S. Pat. Nos. 5,260,069, and 4,871,549 are distinct from the present invention in that they relate to controlled release dosage forms. Herein the dose of the drug is divided in multiple units and there is no specific and particular requirement of assurance that a unit ruptures at a predetermined time in a reliable manner. Statistically, different units rupture at different times and thereby provide controlled release of the active ingredient, on an average, over a period of time. In the present invention, the total amount of active ingredient is contained in one single unit and is intended to be released at the predetermined time. An important requirement for using such systems in a large number of patients is that the system should deliver the drug at about the predetermined time in a reliable manner to the large number of patients to whom the system is administered. Thus, the coat rupture should occur reliably and consequently drug should be released reliably. For instance, if in five to ten out of a hundred times the coatings do not open or rupture at about the predetermined time, but rupture at a significantly prolonged time when tested by agitation over a range of agitational conditions and aqueous compositions, then the desired release at the predetermined time is not achieved reliably. Also, if the release prior to rupture may be influenced by changes in pH, then the desired release at the predetermined time is not achieved reliably. Also, if the coat rupture occurs but the therapeutically active agent is not released as a pulse in all or some of the units, then the desired release as a pulse at a predetermined time is not achieved reliably. Prior arts such as WO 99/18938, WO 00/74655, and IE 902533 make no reference to reliability of rupture or release from a large number of tablets or to the process for optimizing the compositions to obtain the reliability of rupture or reliability of release over a large number of tablets. U.S. Pat. No. 5,229,131 presents a large amount of data giving the percent tablets splitting at 30 min and 60 min and the percent tablets releasing their contents at 60 min and 120 min in Tables 12 to 18. The tablets do not provide reliable manner of rupture as provided by the composition of the present invention, wherein 36 out of 36 tablets rupture within ±50% of the coating failure time. Despite the plethora of prior art, there are no commercially successful systems that provide spaced drug delivery in a reliable manner.        
The prior art does not mention any formulations or systems containing combinations of two or more therapeutically active antidiabetic agents, wherein at least one therapeutically active antidiabetic agent is released immediately and at least one therapeutically active agent is released after a lag period or a predetermined spacing interval.